The proposed work will focus on the synthesis of complex natural products through the application of novel reaction pathways. Natural products to be pursued during the requested funding period are azaspiracid, pelletierine, lycopodine, lycoperine, cermizine D, himeradine A, and amphidinolides B2 and C. Each of these compounds possesses a daunting synthetic architecture with features that are not well addressed by current synthetic methods. We will work to complete the total synthesis of azaspiracid-1 utilizing on our considerable previous work on this target. In our alkaloid projects, we have developed a series of new organocatalyzed reactions that we intend to apply to their construction. Our efforts toward the lycopodine family of alkaloids (lycopodine, lycoperine, himeradine) will employ novel amine-catalyzed, intramolecular Michael addition strategy to construct the key cyclohexanone ring. Another key step in this series of compounds will be a tandem 1,3-shift of alpha iminyl sulfone / intramolecular Mannich cyclization which we have recently discovered. We will exploit another methodology developed within our laboratory, an organocatalyzed, intramolecular heteroatom Michael addition reaction, for the synthesis of cermizine D. Our synthetic endeavors towards himeradine A will combine our organocatalyzed technologies to construct its dense heptacyclic ring system. On our macrolide projects, we will work to establish the correct structure of amphidinolide B2 utilizing our considerable previous work toward the amphidinolide B subfamily. Finally, our amphidinolide C work will utilize a tandem gold-catalyzed enol ether formation / 5-endo cyclization to form the two trans-furan rings found in the natural product through a common intermediate. We will also employ our HWE technology for the construction of the highly substituted C9-C11 diene moiety. We will have our synthesized amphidinolide compounds will be evaluated for anti-cancer activity to probe the SAR of these compounds. Additionally, intermediates from of our synthetic routes will be submitted to the NIH Molecular Libraries Small Molecule Repository (MLSMR) to be used for high throughput screening by the NIH's Molecular Libraries Screening Centers Network (MLSCN). PUBLIC HEALTH RELEVANCE: Our research program provides several tangible benefits toward the NIH's mission of public health. Our synthetic routes to biologically active natural products help to provide access to interesting compounds for screening of their medicinal importance. In addition, our new strategies for the synthesis of natural products open new doors for other researchers to new carbon-carbon and carbon-heteroatom bond forming reactions.